The identification of small organic molecules that affect specific biological functions is an endeavor that impacts both biology and medicine. Such molecules are useful as therapeutic agents and as probes of biological function. In but one example from the emerging field of chemical genetics, in which small molecules can be used to alter the function of biological molecules to which they bind, these molecules have been useful at elucidating signal transduction pathways by acting as chemical protein knockouts, thereby causing a loss of protein function. (Schreiber et al., J. Am. Chem. Soc., 1990, 112, 5583; Mitchison, Chem. and Biol., 1994, 1, 3) Additionally, due to the interaction of these small molecules with particular biological targets and their ability to affect specific biological function, they may also serve as candidates for the development of therapeutics. One important class of small molecules, natural products, which are small molecules obtained from nature, clearly have played an important role in the development of biology and medicine, serving as pharmaceutical leads, drugs (Newman et al., Nat. Prod. Rep. 2000, 17, 215-234), and powerful reagents for studying cell biology (Schreiber, S. L. Chem. and Eng. News 1992 (Oct. 26), 22-32).
Because it is difficult to predict which small molecules will interact with a biological target, intense efforts have been directed towards the generation of large numbers, or libraries, of small organic compounds. These libraries can then be linked to sensitive screens to identify the active molecules. Of particular interest has been the development of libraries based upon existing natural products. To date, however, libraries based on natural products have been synthesized primarily for the purpose of improving the known biological and pharmacokinetic properties of the parent natural products (Hall, D. G.; Manku, S.; Wang, F. J. Comb. Chem. 2001, 3(2), 125-150; Nicolaou, K. C.; Vourloumis, D.; Li, T.; Pastor, J.; Winssinger, N.; He, Y.; Ninkovis, S.; Sarabia, F.; Vallberg, H.; Roschanger, F.; King, N. P.; Finlay, R. V.; Giannakakou, P.; Verdier-Pinard, P.; Hamel, E. Angew. Chem., Int. Ed. Engl. 1997, 36, 2097-2103; Nicolaou, K. C.; Winssinger, D.; Vourloumis, D.; Ohshima, T.; Kim, S.; Pfefferkoth, J.; Xu, J.-Y.; Li, T. J. Am. Chem. Soc. 1998, 120, 10814-10826; Lee, K. J.; Angulo, A.; Ghazal, P.; Janda, K. D. Org. Lett. 1999, 1, 1859-1862; Xu, R.; Greiveldinger, G.; Marenus, L. E.; Cooper, A.; Ellman, J. A. J. Am. Chem. Soc. 1999,121, 4898-4899; Wipf, P.; Reeves, J. T.; Balachandran, R.; Giuliano, K. A.; Hamel, E.; Day, B. W. J. Am. Chem. Soc. 2000, 122, 9391-9395; Boger, D. L.; Fink, B. E.; Hedrick, M. P. J. Am. Chem. Soc. 2000, 122, 6382-6394; Nicolaou, K. C.; Pfefferkorn, J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122, 9968-9976 and references cited therein).
Clearly, as detailed above, a great deal of research has been conducted to optimize existing natural product leads, the development of compounds and libraries of compounds based upon natural products and/or emulating the structural and stereochemical diversity of natural products, but having different biological activities than the parent natural product, would also be useful. Additionally, the development of novel synthetic methodologies would assist in the development of new classes of complex compounds and libraries of compound. In order achieve greater diversity and complexity in the synthesis of compounds and particularly libraries of compounds, it would be desirable to develop such methods by either utilizing or emulating the rapid and stereoselective pathways that nature uses in the synthesis of natural products for the efficient production of complex compounds and libraries of compounds. Any resultant novel complex compounds and libraries based on biomimetic pathways will certainly be useful in the quest to discover either non-natural compounds having the binding affinities and specific characteristics of natural products, themselves the products of genetic recombination and natural selection, or will be particularly useful in the quest to discover compounds based upon natural products that exhibit novel biological properties.
In one aspect of the invention, novel compounds having the structure (I) are provided: 
wherein R1 is hydrogen or halogen, or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety or is SRA, N(RA)2, or ORA, wherein RA is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein R2 is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted, or R2 is a solid support optionally attached through a linker moiety;
wherein R3 is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl, or alkylheteroaryl moieties may be substituted or unsubstituted; or wherein R3 is xe2x80x94CN; xe2x80x94O(CN)Rx; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); xe2x80x94CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(Rx)2; xe2x80x94S(O)2Rx; wherein each occurrence of R1 is aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents may be substituted or unsubstituted;
wherein R4 is is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein R5 is hydrogen, halogen, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)Rx, xe2x80x94CO2(Rx), xe2x80x94CON(Rx)2, xe2x80x94OC(O)Rx, xe2x80x94OCO2Rx, xe2x80x94OCON(Rx)2, xe2x80x94N(Rx)2, xe2x80x94S(O)2Rx, wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted; or R5 is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, or is SRA, N(RA)2, or ORA, wherein RA is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein X is O, S or NR6, wherein R6 is OR7, NHR7, or NH(S(xe2x95x90O)2)R7, wherein R7 is aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted; and
wherein the dotted line indicates the absence of a bond or indicates a bond, whereby a single bond or double bond is present, respectively.
In certain embodiments, compounds having the structure (II) are provided: 
wherein RA is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein R2 is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted, or R2 is a solid support optionally attached through a linker moiety;
wherein R3 is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl, or alkylheteroaryl moieties may be substituted or unsubstituted; or wherein R3 is xe2x80x94CN; xe2x80x94O(CN)Rx; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); xe2x80x94CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(Rx); xe2x80x94S(O)2Rx; wherein each occurrence of Rx is aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents may be substituted or unsubstituted, branched or unbranched; cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents may be substituted or unsubstituted;
wherein R4 is is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein R5 is hydrogen, halogen, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)Rx, xe2x80x94CO2(Rx), xe2x80x94CON(Rx)2, xe2x80x94OC(O)Rx, xe2x80x94OCO2Rx, xe2x80x94OCON(Rx)2, xe2x80x94N(Rx)2, xe2x80x94S(O)2Rx, wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted; or R5 is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, or is SRA, N(RA)2, or ORA, wherein RA is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted; and
wherein R6 is OR7, NHR7, or NH(S(xe2x95x90O)2)R7, wherein R7 is aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.
In yet other embodiments, collection of compounds comprising two or more of the compounds of structures (I) or (II) are provided. In certain embodiments, the collection is provided in array format. In yet other embodiments, the collection is provided in array format on a glass slide. In still other embodiments, the collection comprises at least 100 compounds. In yet other embodiments, the collection comprises at least 1,000 compounds. In still further embodiments, the collection comprises at least 2,000 compounds. In yet other embodiments,the collection comprises at least 10,000 compounds.
In another aspect of the invention, a method for the synthesis of the core structure (III) is provided, said method comprising:
providing two phenolic precursors having the structures: 
subjecting the two phenolic precursors to suitable conditions to generate an intermediate having the structure: 
subjecting the intermediate to suitable conditions to effect oxidation and subsequent cyclization to generate a scaffold having the core structure (III): 
wherein R2 is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted, or R2 is a solid support optionally attached through a linker moiety
wherein R5 is hydrogen, halogen, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)Rx, xe2x80x94CO2(Rx), xe2x80x94CON(Rx)2, xe2x80x94OC(O)Rx, xe2x80x94OCO2Rx, xe2x80x94OCON(Rx)2, xe2x80x94N(Rx)2, xe2x80x94S(O)2Rx, wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted; or R5 is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, or is SRA, N(RA)2, or ORA, wherein RA is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted; and
wherein P is an oxygen protecting group.
In certain embodiments, the method further comprises subjecting the core structure (III) to one or more diversification reactions to generate one or more compounds having the structure (I): 
wherein R1 is hydrogen or halogen, or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety or is SRA, N(RA)2, or ORA, wherein RA is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein R2 is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted, or R2 is a solid support optionally attached through a linker moiety;
wherein R3 is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl, or alkylheteroaryl moieties may be substituted or unsubstituted; or wherein R3 is xe2x80x94CN; xe2x80x94O(CN)Rx; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); xe2x80x94CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(Rx)2; xe2x80x94S(O)2Rx; wherein each occurrence of Rx is aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents may be substituted or unsubstituted;
wherein R4 is is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein R5 is hydrogen, halogen, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)Rx, xe2x80x94CO2(Rx), xe2x80x94CON(Rx)2, xe2x80x94OC(O)Rx, xe2x80x94OCO2Rx, xe2x80x94OCON(Rx)2, xe2x80x94N(Rx)2, xe2x80x94S(O)2Rx, wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted; or R5 is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, or is SRA, N(RA)2, or ORA, wherein RA is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein X is O, S or NR6, wherein R6 is OR7, NHR7, or NH(S(xe2x95x90O)2)R7, wherein R7 is aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted; and
wherein the dotted line indicates the absence of a bond or indicates a bond, whereby a single bond or double bond is present, respectively.
In yet another embodiment, the method further comprises subjecting the core structure (III) to one or more diversification reactions to generate one or more compounds having the structure (II): 
wherein RA is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein R2 is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted, or R2 is a solid support optionally attached through a linker moiety;
wherein R3 is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl, or alkylheteroaryl moieties may be substituted or unsubstituted; or wherein R3 is xe2x80x94CN; xe2x80x94O(CN)Rx; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(Rx)2; xe2x80x94S(O)2Rx; wherein each occurrence of Rx is aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents may be substituted or unsubstituted;
wherein R4 is is hydrogen or is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted;
wherein R5 is hydrogen, halogen, xe2x80x94NO2, xe2x80x94CN, xe2x80x94C(O)Rx, xe2x80x94CO2(Rx), xe2x80x94CON(Rx)2, xe2x80x94OC(O)Rx, xe2x80x94OCO2Rx, xe2x80x94OCON(Rx)2, xe2x80x94N(Rx)2, xe2x80x94S(O)2Rx, wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted; or R5 is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl moiety, or is SRA, N(RA)2, or ORA, wherein RA is an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, and wherein each of the aliphatic and heteroaliphatic moieties may be substituted or unsubstituted, cyclic or acyclic, or branched or unbranched, and wherein each of the aryl, heteroaryl, alkylaryl or alkylheteroaryl moieties may be substituted or unsubstituted; and
wherein R6 is OR7, NHR7, or NH(S(xe2x95x90O)2)R7, wherein R7 is aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted.
In yet another aspect of the invention, pharmaceutical compositions are provided comprising any one of the compounds described above and herein; and a pharmaceutically acceptable carrier or diluent.
In still another aspect of the invention, methods of treating a variety of disorders are provided comprising administering a therapeutically effective compound or composition thereof to a subject in need thereof. In certain embodiments, the inventive compounds are utilized to effect wound healing. In certain other embodiments, the inventive compounds are utilized to treat proliferative disorders, including, but not limited to cancer. In certain other embodiments, the inventive compounds are utilized to treat reproductive disorders. In still other embodiments, the inventive compounds are utilized to treat bacterial or protozoal infections.
This invention provides a new family of compounds with a range of biological properties. Compounds of this invention have biological activities relevant for the treatment of diseases including proliferative diseases such as cancer, wound healing, and bacterial infections to name a few. Compounds of this invention include those specifically set forth above and described herein, and are illustrated in part by the various classes, subgenera and species disclosed elsewhere herein.
It will be appreciated by one of ordinary skill in the art that asymmetric centers may exist in the compounds of the present invention. Thus, inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. In certain embodiments, the compounds of the invention are enantiopure compounds. In certain other embodiments, a mixtures of stereoisomers or diastereomers are provided.
Additionally, the present invention provides pharmaceutically acceptable derivatives of the inventive compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional therapeutic agents. The phrase, xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d, as used herein, denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof. Pharmaceutically acceptable derivatives thus include among others pro-drugs. A pro-drug is a derivative of a compound, usually with significantly reduced pharmacological activity, which contains an additional moiety which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species. An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest. Pro-drugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs, are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
Certain compounds of the present invention, and definitions of specific functional groups are also described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in xe2x80x9cOrganic Chemistryxe2x80x9d, Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference. Furthermore, it will be appreciated by one of ordinary skill in the art that the synthetic methods, as described herein, utilize a variety of protecting groups. By the term xe2x80x9cprotecting groupxe2x80x9d, has used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at another reactive site in a multifunctional compound. In preferred embodiments, a protecting group reacts selectively in good yield to give a protected substrate that is stable to the projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other functional groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction. As detailed herein, oxygen, sulfur, nitrogen and carbon protecting groups may be utilized. Exemplary protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present invention. Additionally, a variety of protecting groups are described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d Third Ed. Greene, T. W. and Wuts, P. G., Eds., John Wiley and Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term xe2x80x9csubstitutedxe2x80x9d whether preceded by the term xe2x80x9coptionallyxe2x80x9d or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term xe2x80x9csubstitutedxe2x80x9d is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. Furthermore, this invention is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example of proliferative disorders, cancer, wound healing, infectious diseases, and immunological diseases. The term xe2x80x9cstablexe2x80x9d, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
The term xe2x80x9caliphaticxe2x80x9d, as used herein, includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, xe2x80x9caliphaticxe2x80x9d is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. Thus, as used herein, the term xe2x80x9calkylxe2x80x9d includes both straight, branched and cyclic alkyl groups. An analogous convention applies to other generic terms such as xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d and the like. Furthermore, as used herein, the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d and the like encompass both substituted and unsubstituted groups.
In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups employed in the invention contain 1-4 aliphatic carbon atoms. Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, xe2x80x94CH2-cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, xe2x80x94CH2-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, xe2x80x94CH2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, xe2x80x94CH2-cyclohexyl moieties and the like, which again, may bear one or more substituents. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
The term xe2x80x9calkoxyxe2x80x9d, or xe2x80x9cthioalkylxe2x80x9d as used herein refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom. In certain embodiments, the alkyl group contains 1-20 alipahtic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkoxy, include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy. Examples of thioalkyl include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
The term xe2x80x9calkylaminoxe2x80x9d refers to a group having the structure xe2x80x94NHRxe2x80x2 wherein Rxe2x80x2 is alkyl, as defined herein. In certain embodiments, the alkyl group contains 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl group contains 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains 1-4 aliphatic carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.
Some examples of substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; xe2x80x94OH; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CF3; xe2x80x94CH2CF3; xe2x80x94CHCl2; xe2x80x94CH2OH; xe2x80x94CH2CH2OH; xe2x80x94CH2NH2; xe2x80x94CH2SO2CH3; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); xe2x80x94CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(Rx)2; xe2x80x94S(O)2Rx; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples which are described herein.
In general, the terms xe2x80x9carylxe2x80x9d and xe2x80x9cheteroarylxe2x80x9d, as used herein, refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted. Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound. In certain embodiments of the present invention, xe2x80x9carylxe2x80x9d refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. In certain embodiments of the present invention, the term xe2x80x9cheteroarylxe2x80x9d, as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
It will be appreciated that aryl and heteroaryl groups (including bicyclic aryl groups) can be unsubstituted or substituted, wherein substitution includes replacement of one, two or three of the hydrogen atoms thereon independently with any one or more of the following moieties including, but not limited to: aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; xe2x80x94OH; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CF3; xe2x80x94CH2CF3; xe2x80x94CHCl2; xe2x80x94CH2OH; xe2x80x94CH2CH2OH; xe2x80x94CH2NH2; xe2x80x94CH2SO2CH3; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); xe2x80x94CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(R)2; xe2x80x94S(O)2Rx; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substitutents are illustrated by the specific embodiments shown in the Examples which are described herein.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of other aliphatic, heteroaliphatic or hetercyclic moieties, may optionally be substituted with substituents including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; xe2x80x94OH; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CF3; xe2x80x94CH2CF3; xe2x80x94CHCl2; xe2x80x94CH2OH; xe2x80x94CH2CH2OH; xe2x80x94CH2NH2; xe2x80x94CH2SO2CH3; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); xe2x80x94CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(Rx)2; xe2x80x94S(O)2Rx; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substitutents are illustrated by the specific embodiments shown in the Examples which are described herein.
The term xe2x80x9cheteroaliphaticxe2x80x9d, as used herein, refers to aliphatic moieties which contain one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be branched, unbranched or cyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc. In certain embodiments, heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; xe2x80x94OH; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CF3; xe2x80x94CH2CF3; xe2x80x94CHCl2; xe2x80x94CH2OH; xe2x80x94CH2CH2OH; xe2x80x94CH2NH2; xe2x80x94CH2SO2CH3; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); xe2x80x94CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(Rx)2; xe2x80x94S(O)2Rx; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substitutents are illustrated by the specific embodiments shown in the Examples which are described herein.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogenxe2x80x9d as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term xe2x80x9chaloalkylxe2x80x9d denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term xe2x80x9cheterocycloalkylxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d, as used herein, refers to a non-aromatic 5-, 6- or 7-membered ring or a polycyclic group, including, but not limited to a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. In certain embodiments, a xe2x80x9csubstituted heterocycloalkyl or heterocyclexe2x80x9d group is utilized and as used herein, refers to a heterocycloalkyl or heterocycle group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to aliphatic; heteroaliphatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; xe2x80x94OH; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CF3; xe2x80x94CH2CF3; xe2x80x94CHCl2; xe2x80x94CH2OH; xe2x80x94CH2CH2OH; xe2x80x94CH2NH2; xe2x80x94CH2SO2CH3; xe2x80x94C(O)Rx; xe2x80x94CO2(Rx); xe2x80x94CON(Rx)2; xe2x80x94OC(O)Rx; xe2x80x94OCO2Rx; xe2x80x94OCON(Rx)2; xe2x80x94N(Rx)2; xe2x80x94S(O)2Rx; wherein each occurrence of Rx independently includes, but is not limited to, aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl, wherein any of the aliphatic, heteroaliphatic, alkylaryl, or alkylheteroaryl substituents described above and herein may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and wherein any of the aryl or heteroaryl substituents described above and herein may be substituted or unsubstituted. Additional examples of generally applicable substitutents are illustrated by the specific embodiments shown in the Examples which are described herein.
The term xe2x80x9csolid supportxe2x80x9d, as used herein, refers to a material having a rigid or semi-rigid surface. Such materials will preferably take the form of small beads, pellets, disks, chips, dishes, multi-well plates, glass slides, wafers, or the like, although other forms may be used. In some embodiments, at least one surface of the substrate will be substantially flat. The term xe2x80x9csurfacexe2x80x9d refers to any generally two-dimensional structure on a solid substrate and may have steps, ridges, kinks, terraces, and the like without ceasing to be a surface.
The term xe2x80x9cpolymeric supportxe2x80x9d, as used herein, refers to a soluble or insoluble polymer to which an amino acid or other chemical moiety can be covalently bonded by reaction with a functional group of the polymeric support. Many suitable polymeric supports are known, and include soluble polymers such as polyethylene glycols or polyvinyl alcohols, as well as insoluble polymers such as polystyrene resins. A suitable polymeric support includes functional groups such as those described below. A polymeric support is termed xe2x80x9csolublexe2x80x9d if a polymer, or a polymer-supported compound, is soluble under the conditions employed. However, in general, a soluble polymer can be rendered insoluble under defined conditions. Accordingly, a polymeric support can be soluble under certain conditions and insoluble under other conditions.
The term xe2x80x9clinkerxe2x80x9d, as used herein, refers to a chemical moiety utilized to, attach a compound of interest to a solid support to facilitate synthesis of inventive compounds. Exemplary linkers are described in Example 2, as described herein. It will be appreciated that other linkers (including silicon-based linkers and other linkers) that are known in the art can also be employed for the synthesis of the compounds of the invention.